6-fluoro-9alpha-halo-11-oxygenated-4-pregnenes and 6-fluoro-9alpha-halo-11-oxygenated-1,4-pregnadienes



United States Patent 6-FLUOR0-9cz-HALO 11 0XYGENATED'-4-PREG- NENES AND 6 FLU0RQ-9u-HALO-1l-OXYGEN- ATED-1,4-PREGNADIENES J Allan Campbell, Kalamazoo 'Townsliip, Kalamazoo County, John 'C. Babcock, Portage Township, fK'alamazoo County, and John A. 'Hogg, Kalamazoo Township, Kalamazoo County, :Mich., assignors to The Upjohn Company, Kalamazoo, Mich., acorporation of Michigan I No Drawing. Application June/9, 1958 Serial No. 740,591

31 Claims. v (Cl.260-23955) C=O CH3 7 a wherein the 1,2-carbon atom linkage is selected .from the linkages consisting of single bond and double .bond ilinkages, -R represents hydrogen or the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, X is selected from the group consisting of the carbonyl radical C:O.) and the :hydroxymethylene radical OHOH) and Y is a halogen having an atomic weight of from nineteen to eighty, inclusive.

In this application the wavy line (Z) appearing at the 6-position is a generic expression including the alpha (a) and beta 3 configuration.

The compounds of Formula I possess useful therapeutic properties, They possess glucocorticoid activity and antiphlogistic activity, being useful in the treatment of inflammatory diseases, e. -g., rheumatoid arthritis. In

addition to anti-inflammatory activity they ;produce a favorable body electrolyte balance which makes them especially valuable for oral and parenteral as well as topical use. They are useful in the treatment" of inflammatory conditions of the skin, eyes and ears of humans and of valuable domestic animals, as well as contact dermatitis and other allergic reactions. Compositions containing the compounds of the present invention can be prepared for human or animal use by incorporating them in any one of the several dosage forms suitable forsuch use. Administration of the novel steroids thus can be in conventional dosagev forms, such as pills, tabletsf c'apsules, solutions, syrups or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic cortical steroid'hormones for injectable products.

The novel compounds of Formula I can also be administered topically in the form of ointments, creams, lotions, and "the like, with or withou't' coacting antibiotics, germi'cides, or othermaterials forming advantageous combinations therewith. 1

The starting compounds for itheproc'esses-of the present invention, for example, -.6o+fiuoro- 11}8,2l-dihydroxy l :pregnene-SQO-di'one and the .2 1'a'c-yla'tes -thereof, 678- -fluoro-1.l;3,'21-dihydroxy-4-pregnene-3,20-dione and {the 21-acylates thereof, :are disclosed in'ourcopending application :Serial No. 699,507., file'cLNovember 29, 1957, new

:Patent No. 2,838,540,issued June 10, 8.

The novel compounds of :the present invention can be prepared Lin accordance with the vfollowing reaction scheme:

I CH;

'GHaO'll CE: I CH2 OR wherein R and Y have the same meaning as previously givenpand W is. a halogen having an atomic weight of from 35 to 127 inclusive.

One of the novel processes'of this invention, depicted schematically above, comprises first the dehydration of .6 -fluoro-1 113,21-dihydroxy-4-pregnene-3 ,ZO-dione (and the ZI-acylat'es thereof) to obtain 6-fluoro-21-hydroxy- 4,9(11)-pregnadiene-3,20-dione (and the 21-acylates thereof), followed by treatment of the dehydration prodnet with a source of hypohalous acid in which the halogen -is'brornine, chlorine, or iodine to produce the correspond- 6-fluo'ro-9a-halo-l 13,21-dihydroxy-4-pregnene-3,20- dione (and the 2l-acylates thereof). The said.9a-halo compound is then epoxidized with a mild base to give 6- fluoro-9p,11,8-oxido-21-hydroxy-4-pregnene 3,20 dione (and the 21-acylates thereof). Cleavage of the said 9,11- oxiclo compoundwith a hydrogen halide or a hydrogen I halo-21-hydroxy-4-pregnene-3,11,20-trione with microhalide-releasing agent providing a source of hydrogen fluoride, hydrogen chloride, or hydrogen. bromide, gives the corresponding 6-fiuoro-9u-halo-l15,21-dihydroxy-4- pregfi'e'n-3,20-dione (and the 21-acylat'es thereof) which can'be oxidized,'by known methods for the oxidation of the ll-hydroxy to ll-keto group, to produce 6-fluoro-9ahalo-2 1-.hydroxy 4-pregnene-3,11,20-trione (and "the 21 acylates thereof) y 6 fluoro-9a-halo-1113,21-dihydroxy-4-pregnene 3,20-

7 dione (and the 21-acy1ates thereof) and 6-fluoro-9a-halo- 2l-hydroxy-4-pregnene-3,11,20-trione (and the 21-acylates thereof) can then be subjected to biological dehydrogenation using microorganisms, for example, Septomyxa, or to chemical dehydrogenation using'selenium dioxide, to produce the corresponding A analogues thereof, namely, 6-fluoro-9a-halo-115,21-di hydro'xy-1,4-pregnadiene-3,20-dione (and the 21-acylates thereof) and 6-fluoro-9a-halo-l,4-pregnadiene-3,l1,20- trione (and the Zl-acylates thereof), respectively.

Alternatively, 6-fluoro-9a-halo-2l-hydroxy-1,4 pregnadiene-3,11,20-tri'one (and the-'21-acylates thereof) can be obtained from 6-fluoro-9a-halo-115,21-dihydroxy-L4- pregnadiene-3,20-dione (and the 21-acylates thereof) by oxidation using known methods for the oxidation of the ll-hydroxy group to the ll-keto group.

Treatment of the 21-acylates of 6-fluoro-9a-halo- 11p,21-dihydroxy-4-pregnene-3,20-dione and 6-fit101O-9uorganisms to effect dehydrogenation at the A -position also generally effects removal of the 21-acylate group producing a reaction mixture which contains primarily the corresponding A -21-hydroxy steroid. The A -2lhydroxy steroid thus obtained can be esterified in accordance with procedures known in the art and discussed in greater detail below.

When chemical dehydrogenation using selenium dioxide is the method used to introduce the A -bond, the 21-acylates of 6-fluoro-9ot-halo-115,21-dihydroxy-4-pregnone-3,20-dione and 6-fluoro-9a-halo-21-hydroxy-4-pregnene-3,11,20-trione are the preferred steroids used in the reaction, yielding the corresponding A -21-acylate compounds directly.

In carrying out one of the novel processes of this invention, 6-fluorol15,21-dihydroxy-4-pregnene-3,20-dione (and the 21-acylates thereof) (II), is dehydrated to 6- fluoro-21-hydroxy-4,9 1 1 )-pregnadiene-3,20-dione (and the 21-acylates thereof) (III) by methods known in the art, e. g., by a dehydrating agent such as phosphorus oxychloride, thionyl chloride, hydrochloric acid or sulfuric acid and-acetic acid. The dehydration is generally effected by the preferred method of reacting the 6-fluorol16,21-dihydroxy-4-pregnene-3,ZO-dione 21-acylates (II) with a carboxylic acid N-haloamide or N-haloimide, wherein the halogen is bromine or chlorine, in an organic base either with or followed by anhydrous sulfur dioxide. Examples of such N-haloamides or N-haloimides are N-chloroacetamide, N-bromoacetamide, N- chlorosuccinimide, N-bromosuccinimide, 3-bromo-5,5- dirnethylhydantoin, 1,3-dibromo-5,S-dimethylhydantoin, and the like, N-bromoacetamide being preferred. The organic bases employed as solvents in the above reaction are generally tertiary amines wherein the amino nitrogen is a member of an aromatic ring, such as the pyridines and lower fatty amides, pyridine being preferred. Normally an amount in excess of a molar equivalent of organic base calculated on the basis of the quantity of starting steroid is employed. The sulfur dioxide is advantageously employed in substantially anhydrous form, inasmuch as the presence of water tends ployed, the specific temperature at which the reaction is conducted being determinative of the reaction time. 6- fluoro-21-hydroxy-4,9 1 1)-pregnadiene-3 ,20-dione is obtained by the hydrolysis of 6-fluoro-21-hydroxy-4,9(11)- pregnadiene-3,20-dione 21-acylates according to procedures well known in the art.

The thus-obtained dehydration product is converted to 6 fluoro 9oz halo 115,21 dihydroxy 4 pregnene- 3,20-dione (and the 21-acylates thereof) (IV) by reaction with a hypohalous acid. The hypohalous acid is usually produced in situ by reaction of an acid with N- haloamide or N-haloimide wherein the halogen is bromine, chlorine or iodine. The 6-fluoro-2l-hydroxy-4,9(11)- pregnadiene-3,20-dione (and the 21-acylates thereof) (III) is dissolved in an organic solvent such as methylene chloride, tertiary butyl alcohol, dioxane, tertiary amyl alcohol, or the like, and reacted at room temperature with the hypohalous acid releasing agent, which includes N-bromoacetarnide, N-chloroacetamide, N-bromosuccinimide, N-iodosuccinimide, N -chlorosuccinimide, and the like, in the presence of an acid such as perchloric acid, dilute sulfuric acid, and the like. .N-bromoacetameme- 19 S tnide in tertiary butyl alcohol with perchloric acid and water are the preferred reagents for this reaction. Normally the halogenation is'conducted at room temperatures, between fifteen and thirty degrees centigrade, although temperatures on either side of this range are operative. The reaction period may vary from about five minutes to one hour. At the conclusion of the desired reaction, the excess hypohalous acid is destroyed by the addition of sulfites or hydrosulfites, sodium sulfite being normally employed. The resulting 6-fluoro- 9a halo 1113,21 --dihydroxy 4 pregnene 3,20- dione (and the 21-acylates thereof) (IV), in which the halogen is bromine, chlorine, or iodine, can be isolated from the reaction mixture by adding an excess of water and extracting the product with organic solvents or by recovering the precipitated compound by filtration. The crude reaction product may be employed directly in the next step of the process. v

The 9a-halo compound (IV) as defined above is then dehydrohalogenated with a weak base, potassium acetate being preferred. The reaction is conducted in an inert solvent such as methanol, ethanol, acetone, dioxane, and the like. The dehydrohalogenation reaction takes place over a rather wide range of temperatures, normally from about minus fifteen degrees to the boiling point of the reaction mixture, the range between zero "degrees and sixty degrees centigrade being most convenient. The reaction time may be varied considerably, depending on the temperature employed, a period of reflux of from about eight to twenty hours producing satisfactory yields, with about eighteen hours usually being suflicient. The reaction mixture'is concentrated, cooled and precipitated with water to give 6 fluoro 95,113 oxido 21 hydroxy-4-pregnene-3,20-dione (and the 2l-acylates thereof) (V). A

In the epoxide opening step, the 9,11-oxido compound '(V) is reacted with a hydrogen halide such as hydrogen fluoride, hydrogen chloride or hydrogen bromide, hydrogen fluoride being preferred, to produce the corresponding 6-'fluoro-9u-halo-11 3-hydroxy-4-pregnene-3,20- dione (VI). Advantageously, the steroid is first dissolved in an organic solvent such as tetrahydrofuran, methylene chloride, and the like. The epoxide cleavage with hydrogen halide is usually conducted at temperatures between about minus eighty and plus fifty degrees Centigrade, the preferred limits being between about minus ten and plus 25 degrees centigrade. The reaction time is usually from about one to 24 hours, with one to five hours being required at room temperatures. After the reaction is complete, the mixture is poured into water and neutralized with a dilute base, such as dilute sodium or potassium hydroxide, or a bicarbonate such as sodium bicarbonate, potassium bicarbonate, or the like. The reaction mixture is then extracted'in the usual manner, such as with methylene chloride, and the '6 fluoro 90c halo 116,21 -dihydroxy 4 pregnene- 3,20-dione (and the 21-acylates thereof) (VI) recovered in a purified form by recrystallization or chromatography.

6 fluoro 9a halo 1113,21 dihydroxy 4 pregnene- 3,20-dione 21-acylates (VI) can then be treated with an oxidizing agent, for example, chromium trioxide, potassium dichromate or sodium dichromate, to obtain 6 fluoro 900 halo 21 hydroxy 4 pregnene 3,11, -trione 21-acylate (VII). The oxidation can be carried out by a variety of methods, such as, for example, by oxidizing the 6-fluoro-9ot-halo-11fi,21-dihydroxy-4- pregnene-3,20-dione ZI-acylates (VI) in acetic acid solution with chromium trioxide or sodium dichromate, or by oxidizing with chromium trioxide in the presence of pyridine. At the conclusion ofthe desired oxidation reaction, the excess chromic acid is generally destroyed by the addition of methyl alcohol, ethyl alcohol, and the like. Thereafter, the resulting '6-fluoro-9u-halo-21- hydroxy-4-pregnene-.3,11,20 trione 21-acyl-a'te's (VI-I) are recovered by conventional means, for example, by pre- Eipitation with water, or extraction with water i'rnmi'slcible solvents, e. g., methylenetliloride, et'her, benzene, toluene, or the like, and purified by crystallization or chromatography. 6 fluoro 9a halo "21 -'hydroxyt 'pregnene-il1,20 trione is obtained by the hydrolysis of 6 fluoro c halo 21 -'"hydroxy '4 pregnene- 3,11,20-trione 2l-acylates according to procedures well known in the art for the saponification of hydrocortisone 21-acetate.

6 -fluoro 9a halo 11 3,21 dihydroxy 4 pregnene- 3,20 dione (and the 21-acy1ates thereof) (VI) and 6 fluoro 9a halo 21 hydroxy 4 pregnene 3,11, 20-trione (and the 21-acylat'es thereof) (VII) are converted to the d -analogues thereof, 6-fl110I'O-9a-h810- 11 3,21 dihydroxy 1,4 pregnadiene 3,20 dione (and the 21-acylates thereof) (VIII) and 6-fluoro-9u-halo-2lhydroxy-1,4-pregnadiene-3,11,20-trione (and the 21-acylates thereof) (IX), respectively, using either fermentative or chemical dehydrogenation. Microorganisms such as Septomyxa, Corynebacterium, Fusarium, and the like,

are used under fermentation conditions well known in the art (e. g., -U. S. 2,602,769) and illustrated ingreater detail below. Where Septomyxa is used to effect the dehydrogenation of the compounds of Formula VI it is found to be advantageous to use with the substrate and medium a steroid promoter, such as progesterone, 3-ketobisnor- 4-cholen-22-al, 3-ketobisnorcholenic acid, 115,21- dihydroxy-1,4,17(20)-pregnatriene-3-one, and the like.

When the 21-acylates of 6-fiuoro-9a-halo-l1fl,21-dihydroxy-4-pregnene-3,20-dione or 6u-fluoro-9u-halo-21-hydroxy-4-pregnene-3,11,20-trione are subjected to fermentative dehydrogenation to introduce the A -bond,'removal of the 21-acylate group is generallyeflfected. The A -21- hydroxy steroid can then be subjected to esterification to produce the desired final 21-acy1ate using conventional 21-acylating conditions; Suitable acylating agents are organic carboxylic acids, particularly hydrocarbon carboxylic acids containing from one to twelve carbon atoms, inclusive, or the acid anhydrides and acid halides thereof. For example, a saturated straight-chain aliphatic acid, e. g., formic, acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, tertiary butylacetic, a cycloaliphatic saturated acid, e. g., ,3 cyclopentylpropio-nic, cyclohexane carboxylic, cyclohexylacetic, an alkaryl acid, e. g., 'benzoic, phenylacetic, p-phenylpropionic, 0-, m-, and p-toluic, a saturated dibasic acid (which can be converted into Water-soluble, e. g., sodium, salts), e. g., succinic, adipic; a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, undec'olic, cinnamic; dibasic unsaturated acids (which can be converted into water-soluble, e. g., sodium, salts), e. g., maleic and citraconic, or the acid anhydrides and acid halides thereof, can be used to convert 6 fluoro 9oz halo 1113,21 dihydroxy 1,4 pregnadiene 3,20 dione and 6 fluoro 9a halo 21- hydroxy-1,4-pregnadiene-3,11,20-trione to their corresponding 21-acylates. If the acylating agent is the free acid, the reaction is preferably effected in the presence of an esterification catalyst, for example, p-toluenesulfonyl chloride, trifiuoroacetic anhydride, p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and the like.

The chemical dehydrogenation can be carried out with selenium dioxide using procedures Well known in the art and further illustrated by the examples herein, the 21- acylates being the preferred steroids used inthe reaction.

Alternatively, the 6 fluoro 9a halo --21 hydroxy- 1,4-pregnadiene-3,11,20-trione .21-acylates (IX) are obtained by the oxidation -of 6-fluoro-9a-halo-1113,21-dihydroxy-1,4-pregnadiene-3,20-dione 2l-acylates (VIH), using the same procedures, described above and in greater detail below, for the oxidation of 6-fluoro-9a-halo-11fl, 21-dihydroxy-4-pregnene-3,20-dione 21-acy1ates (VI) to 6 fluoro -59 halo 21 hydroxy 4 pregnene 3,11, 20-trione 2'1-acylates (VII). If desired, the 6-fl1l0r0-9a- 7 halo -21 hydroxy .1, 4 pregnadiene 3,11,20 trione 2l-acylates can be hydrolyzed using procedures well' wherein R, X and Y have the same meaning as previously given. An alternative process for-the preparation of these'compounds is represented by the following reaction scheme:

' CH; CH3

(31110 R (EH20 R C=O (i= I where R=acyl H XI om CH:

(3111011 (2131203. C=O C=O (Eh XIII XII V CH CH ([JHaOR (I7H2O R HO 0H3 wherein R, W and Y have the same meaning as previously given.

The alternative process for the preparation of the A -steroid compounds of the instant invention comprises: the dehydrogenation of 6-fiuoro-115,21-dihydroxy-4-pregnene-3,20-dione (and the 21-acylates thereof) (II) to produce 6 fluoro-l LB-hydroxy-l,4-pregnadiene 3,20 dione (and the 2l-acylates thereof) (XI) following the procedures used to convert the 9a-halo-11fi,21-dihydroxy steroid (and the 21-acylates thereof) (VI) to the A -9rz-halo-1lfi,21- dihydroxy steroid (and the 21-acy1ates thereof) (VHI). The thus-obtained A -11fi,21-dihydroxy steroid (and the 21-acylates thereof) (XI) is then dehydrated to yield 6- fluoro 21 hydroxy 1,4,9(l1) pregnatriene-3,20-dione (and the 21-acylatesthereof) (XII) in the same manner that is used to dehydrate the 115,21-dihydroxy steroid starting compound (and the 21-acylates thereof) (II) ,to the A -21-hydroxy steroid (and the 21-acylates thereof) (HI). The thus-obtained A -21-hydroxy steroid (and the 21-acy1ates thereof) (XII) is then treated with a source of hypohalou's acid to convert it to 6-fiuoro-9ahalo 115,21 dihydroxy 1,4 pregnadiene 3,20 dione (and the 21-acylates thereof) (XIII) in the same manner that is used to convert the A -21-hydroxy steroid (and the 21-acylates thereof) (III) to the 9a-halo-11B,21-dihydroxy steroid (and the 21-acylates thereof) (IV). The thus-obtained A -9a-ha1o-115,21-dihydroxy steroid (and the 21-acylates thereof) (XIII) is then dehydrohalogenated to convert it to 6-fluoro-9/3,l1/3-oxido-21-hydroxy-1A- pregnadiene-3,20-dione (and the 21-acylates thereof) (XIV) in the same manner that is used to convert the 9a-halo-11B,21-dihydroxy steroid (and the 21-acylates thereof) (IV) to the 95,115-oxido-21-hydroxy steroid (and the 21-acylates thereof) (V). The thus-obtained A 9;8,1l;3-oxido-2l-hydroxy steroid (and the 21-acylates thereof) (XIV) is treated with a hydrogen halide to convert it to 6-fluoro-9a-halo-115,21-dihydroxy-1,4-pregnadiene-3,20-dione (and the 21-acylates thereof) (VIII) in the same manner that is used to convert the 9,8,1 lB-oxido- 21-hydroxy steroid (and the 21-acylates thereof) (V) to the A -9u-halo-115,21-dihydroxy steroid (and the 21-acylates thereof) (VI). The thus-obtained A -9a-halo-11fi,2ldihydroxy 21 -acy1ates (VIII) are then oxidized to convert them to 6-fluoro-9a-halo-2l-hydroxy-1,4-pregnadiene-3, 11,20-trione 21-acylates thereof (IX) in the same manner that is used to convert the 9u-halo-l1B,2l-dihydroxy 21- acylates (VI) to the 9a-halo-11-keto-21-hydroxy 21-acylates (VII).

The foregoing compounds, I through XIV, are all characterized by the presence of a 6-fluoro substituent. It should be noted that the configuration of the fluorine at the 6-position can be either or 6B. Thus on sub stituting 6B-fluoro-11,21-dihydroxy-4-pregnene-3,20-dione as the starting steroid and following the procedures hereinbefore described and as exemplified below produces as the final product of each example the corresponding 6/8-epimer. Where the 6 3-epimer or a mixture predominating therein is employed as the starting material, any subsequent reaction product can be isolated either as the 9 6B epimer or as a mixture of '6'uand 6 8=epimers from which the components can be separatedby chromatography orcrystallization. Alternatively, a 6a-epimeri'zed product can be obtained by treatment of the6B-epimer or mixtures of'the 6aand 6fi-epimers at temperatures near 'zero degrees centigrade, or slightly higher or lower temperatures, in an organic solvent, .such as chloroform, methylene chloride, ether, and the like, and in the presen'ce of a prototropic agent (proton-donating reagent) such as alcohols, organic acids, and the like, with a hydrogen halide such as gaseous hydrogen chloride. The mixture should preferably be maintained at temperatures below zero degrees centigrade during the addition of the hydro gen 'halide. The reaction mixture can then be Washed with'snccessive portions of dilute alkali and water, and then-dried and evaporated under reduced pressure. The '6a-fiuoro products can be recovered from the crude reaction product and purified by recrystallization.

Alternatively, the epimerization'of the 6,8-fiuoro steroids can be accomplished with alkali. Bases, for example, solutions of sodium hydroxide and potassium hydroxide, may be used to treat the 6fi-epimer in solution in an organic solvent, such as methanol, to produce the 60:- epimer.

' As indicated above and described in greater detail be- 'low,"the'sequence of reactions embodied in the processes characterizing this invention is susceptible of variation, theprecise order selected being determined by such factors as economics and convenience.

The following examples are '-illustrative of the process and products of the present invention, but are-not to be construed as limiting. As used in the examples which follow, the 'Roman numeral following'the name of a compound is used to indicate the relation of the compound to the reaction schemes depicted and described above.

EXAMPLE 1 6a.-fluoro-21-hydr0xy-4,9 (11 -pregnadiene-3,20-dione 21 -acetate i (III) droxyl-pregnene-3,20-dione 21-acetate (II) in ten milliliters of pyridine there is added 0.4.gram of N-bromoacetamide. The mixture is allowed to stand under nitrogen for about twenty minutes, at which time itis cooled to approximately five degrees centigrade. While stirring, anhydrous sulfur dioxide is passed over the surface until the-solution gives no color change with acidified starchiodide paper. The temperature of the reaction mixture is not allowed to go above approximately twenty degrees centigrade during the sulfur dioxide addition. The mixtureis then allowed to stand for about five minutes and is poured into 100 milliliters of ice-water, which results in the precipitation of a crude solid. Crystallization from acetone gives 6u-fluoro-21-hydroxy-4,9 1 l)pregnadiene- 3,20-dione ZI-acetate (III), a crystalline solid.

Similarly, the substitution of other 21-acylates of -604- fluoro-l l5,21-dihydroxy-4-pregnene-3,20-dione is productive of the corresponding 2l-acylates of 6a-fluoro-21-hydroxy-4,9( l 1 )-pregnadiene-3,20-dione.

EXAMPLE 1A 6 a-fluoro-Zl -hydr0xy-4,9 (J1 -pregnadiene-3,20-dione Nitrogen is bubbledthrough a solution of 0.33 gram of 6u-fluoro-21-hydroxy-4,9(l1)-pregnadiene-3,20 dione ZI-acetate in 33 millilitersof methanol 'for about fifteen minutes. To this is added'a solution of 0.33 gram of potassium bicarbonate in four milliliters of water, likewise treated with nitrogen. After stirring under nitrogen for about five hours, the base is neutralized by the addition of 2.5 milliliters of five percent hydrochloric acid. The mixture is then concentrated under reduced pressure at fifty degrees centigrade to about five milliliters. The residue is taken up in-ethyl acetate, washed, dried and evaporated to dryness. Crystallization =-from ac'etone-skellysolve B h'e xanes givestSa-fiuoro-fi hydroxyi 4;9 11 -preg'nadiene- 3,20=dione, a "crystalline solid.

In like manner other '21-'acy'1ates of 6m-fluoro-21 hy droxy-4,9(l1) pregn-adiene-3,20-dione 'can he converted to 6u-fluoro-21-hydroxy-4,9(l1)=pregnadiene-3,20-dione.

To a solution of 420 milligrams of'6a-fluo'ro'-2l-hydroxy-4,9(ll)-pregnadiene-3,20-dione ZI-acetate (III) in 6.5 milliliters of methylene chloride there is added milliliters of tertiary butyl alcohol, a solution of 'one milliliter of 72 percent perchloric acid in 7.5 milliliters of water, and a solutionof 182 milligrams of N-b'romo aceta'mide in 3.2 milliliters of tertiary butylual'cohol. After stirring 'for about fiftjeen minutes, a solution of 182'rnillig1ams of sodium sulfite in ten milliliters of'w'ater is added and the mixture concentrated under reduced pressure at approximately sixty degrees centigrade until crystallization occurs. After cooling in an ice bath, thirty milliliters of water is-added with stirring. The crystalline product 'is filtered, washed with water and dried, yielding crystalline 6a'-fluoro-9a-bromo-l1;8,2l-dihydroxy-4epregnene3,20 -dione 21'- acetate (IV). The product was used'i'n the succeedingexample without further purification. 7

Similarly, the substitution of 6a-fluoro-2l-hydroxy- 4,9(1'1.)-pregnadiene=3,20-dione (and other 2l-acylates) is productive of 6u-fluor'o-9a-bromo-1lfl,21-dihydroxy- 3,20-dione (and other 21-acylates).

Substitution of another N-haloamide or an'N lialoimide such as N-iodosuccinimide or N chlorosuc'cinimide for the -N-bromoacetamide in the foregoing reaction is productive of the corresponding 9a-halo product.

A mixture of 2.816 grams of 6u-fluoro-9a-bromol15,21-dihydroxy-4-pregnene 3,20 dione (I-V), 2,8 16 grams of potassium acetate, and ninety milliliters of acetone is stirred and heated at about reflux temperature for approximately eighteen hours. The reaction mixture is then concentratedto about one-half the original volume and cooled in an ice bath. Addition of 250 milliliters of water yields 6a-fluoro-9/8,llfl-oXido-2l-hydroxy-4-pregnene-3,20-dione (V), a crystalline solid, which is recovered by filtration.

Similarly, the substitution of the ZI-acetate (and other 2l-acylates) of 6a-fiuoro-9e-bromo-l1,8,2l-dihydroxy-4- pregnene-3,20'-dione is productive of the 2l-acetate (and other 21 -acylates) of 6a-fiuoro-9p,llB-oxido-Zl-hydroxy- 4-pregnene-3,20-dione.

In like manner, 6oc-fllJOI'O-9oc-Chl0l'O-l 118,21-dihydroxy- 4-pregnene-3,20-dione (and the Zl-acylates thereof) and the 9m-io'do analogue thereof can be converted -to "60:- fluoro-9fi,11 3 oxido-21-hydroxy 4 pregnene 3,20 dione (and the 2l-acylates thereof).

-EXAMPLE 4 To 3.41 grams of liquid hydrogen fluoride and twenty milliliters of methylene chloride cooled in a Dry-Ice bath there is added, portion-wise, a slurry of 1.875 grams of '6m-fiuoro-9Bd1B-oXido-21-hydroxy-4 pregnene 3,20- dione .(V) in 5.97 grams of tetrahydrofuran (distilled over sodium hydroxide) and twenty milliliters of methylene chloride which-had similarly been cooled in a Dry- Ice bath. After standing at approximately zero to five degrees centigrade for about seventeen hours, the reactionmixture is'poured slowly into a stirred mixture of 300. milliliters 'of. ice-water, fifty milliliters of methylene chloride, and twenty grams of sodium bicarbonate. The mixture is stirred for a few minutes, the methylene chloride layer is separated-and the water phase extracted withtwo. 50 -milliliter' portions of fresh methylene chloride. The combined methylene chloride solutions are washed with water, dried, concentrated to 100 milliliters, and poured onto a chromatographic column containing 100 grams of Florisil (synthetic magnesium silicate). The column is eluted with increasing proportions of acetone in Skellysolve B hexanes (100 milliliter fractions). The crystals obtained in allowing the solvent to evaporate from the twenty to 35 percent acetone fractions are recrystallized from acetone-Skellysolve B hexanes to give substantially pure 6,9udifluoro 113,21 dihydroxy 4- pregnene-3,20-dione, a crystalline solid.

Similarly, the substitution of the 21-acetate (and other 2l-acylates) of 6a-fluoro-9fi,11fl-oxido-21-hydroxy-4- pregnene-3,20-dione is productive of the 21-acetate (and other ;21-acylates) of 6a,9u-difluoro-11,8,21-dihydroxy- 4-pregnene-3,20-dione.

Substitution of aqueous hydrogen chloride or hydrogen bromide for the hydrogen fluoride above is productive of the corresponding 9a-halo product.

EXAMPLE 5 21 hydroxy 4 pregnene-3,1I,20- trione ZI-acetate (VII) A solution is prepared containing 0.5 gram of 6u,9otdifluoro 11 6,21 dihydroxy 4 pregnene 3,20 dione 2lacetate (VI), 0.15 gram of chromium trioxide, ten milliliters of glacial acetic acid and one'half milliliter of water. This mixture is stirred and maintained at room temperature for approximately eight hours, after which the reaction is terminated by addition of methanol.

Thereafter, the mixture is poured into fifty milliliters of ice water and the thus-obtained precipitate collected on a filter and recrystallized three times from ethyl acetate andSkellysolve B hexanes to give crystals of 6a,9adifluoro-4-pregnene-3,11,20-trione Zl-acetate (VII).

Similarly, substitution of other 21-acylates of 601,911 difluoro-115,21-dihydroxy-4-pregnene-3,20-dione is productive of the corresponding 21-acylates of 6a,9adifluoro-21-hydroxy-4-pregnene-3,11,20-trione. Treating the 21-acylates of 6a,9u-difluoro-2l-hydroxy-4-pregnene- 3,11,20-trione according to the procedure of Example 1A is productive of 6a,9a-difluoro-21-hydroxy-4-pregnene-3,1 1,20-trione.

Substitution of the corresponding Qa-chloro and 9m bromo starting steroid 21-acyla'te in the above reaction produces 60: fluoro 9oz chloro 4 pregnene 3,11,20- trione 21-acylate and its 9a-bromo analogue, respectively, which, if desired, can be hydrolyzed to 6a-fluoro-9achloro 4 pregnene 3,11,20 trione and its 90: bromo analogue, respectively, by treatment with hydrochloric acid in aqueous methanol.

EXAMPLE 6 6a.,9ot difluoro 1113,21 dihydroxy 1,4-pregnadiene- 3,20-dime (VIII) (biological dehydrogenation) Three 100-milliliter portions of a medium, in 250- milliliter Erlenmeyer flasks, containing one percent glucose, two percent corn steep liquor (sixty percent solids) and tap water, are adjusted to a pH of 4.9. This medium is sterilized for 45 minutes at fifteen pounds per square inch pressure and inoculated with a one to two day growth of Septomyxa afiinis A. T. C. C. 6737. The Erlenmeyer flasks are shaken at room temperature (about 26 to 28 degrees centigrade) for a period of three days. At the end of this period this 300-milli1iter volume is used as an inoculum for five liters of the same glucosecorn steep liquor medium which in addition contained five milliliters of an antifoam compound (a mixture of lard oil and octadecanol). The fermentor is placed into the water-bath, adjusted to 28 degrees centigrade and the contentsstirred (300 R; P. M.) and aerated (0.1 liter perminute of air to ten liters of beer). After twenty hours of incubation, when a good growth has been developed one gram of 6u,9a-difluoro-1113,21-dihydroxy- 4-pregnene-3,20-dione (VI) plus one-half gram of 3- ketobisnor-4-cholen-22-al, dissolved in sixteen milliliters of dimethylformamide is added and the incubation carried out at the same temperature (28 degrees centigrade) and aeration for a period of 72 hours (final pH 8.3). The mycelium was filtered off and extracted with three ZOO-milliliter portions of acetone. The beer was extracted with three one-liter portions of methylene chloride and thereupon the extracts of the beer and acetone are combined, dried over anhydrous sodium sulfate, concentrated to 100 milliliters and poured onto a chromatographic column containing 100 grams of Florisil (synthetic magnesium silicate). The column is eluted with increasing proportions of acetone in Skellysolve B hexanes (100 milliliter fractions). The crystals obtained on allowing the solvent to evaporate from the 25 to 35 percent acetone fractions are recrystallized from acetone-Skellysolve B hexanes to give substantially pure 611,911 difluoro 1118,21 dihydroxy 1,4 pregnadiene- 3,20-dione, a crystalline solid.

Instead of Septomyxa, species of other genera such as Corynebacterium, Didymella, Calonectn'a, Alternaria, Colletotrichum, Cylindrocarpon, Ophiobolus, Fusarium, Listeria, Erysipelothrix, Mycobacterium, Trichothecium, Leptosphaeria, Cucurbitaria, Nocardia, and enzymes of fungi of the family Tuberculariaceae can be used to introduce a A -bond into 6a,9a-difiuoro-11,8,21-dihydroxy- 4-pregnene-3,20-dione.

Similarly, substitution of the corresponding 9a-Chl01'0 or 9a-bromo starting steroid in the above reaction produces 60: fluoro 9o: chloro 115,21 dihydroxy- 1,4 pregnadiene 3,20 dione and its bromo analogue, respectively.

EXAMPLE 6A 6at,9a difluoro 1113,21 dihydroxy 1,4 pregnadiene- 3,20-dime 21 -acetate (VIII) Substituting 60:,90: difluoro 115,21 dihydroxy 4- pregnene-3,20-dione 2l-acetate (and other 21-acylates) for 611,9 difluoro 1119,21 dihydroxy 4 pregnene- 3,20-dione in the procedure of Example 6 is productive of 611,90: difluoro 11,8,21 dihydroxy 1,4-preg-' nadiene-3,20-dione (VIII).

To 0.30 gram of 6a,9a-difluoro-11B,21-dihydr0xy-1,4- pregnadiene-3,20-dione there is added two millilitersof pyridine and 1.5 milliliters of acetic anhydride. The reaction mixture is allowed to stand at approximately 25 degrees centigrade for about eight hours and then poured into forty milliliters of ice-water whereupon a solid precipitates. The thus-obtained mixture is stirred for two hours. The solid product is recovered by filtration, Washed with water, dried and recrystallized from etherhexane to give crystals of 6a,9m-difluorollfi,21- dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate.

Similarly, substitution of the corresponding 9a-ehloro or 9a-bromo starting steroid in the above reactions of Example 6A produces 6a-fluoro-9u-chloro-11,8,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate and its 9a-bromo analogue, respectively.

EXAMPLE 6B 601,90: difluoro 1113,21 dihydroxy 1,4 pregnadiene- 3,20-diam? 21 -hemisuccinate (VIII) A solution is prepared containing 0.5 gram of succinic anhydride and 0.1 gram of 6u,9a-difluoro-1lB,21-dihydroxy-1,4-pregnadiene-3,20-dione (VIII) in five milliliters of pyridine. The solution is allowed to stand for a period of about twenty hours, diluted with water and the thusobtained mixture is refrigerated and then filtered; The precipitate is collected on a filter and recrystallized two times from methanol to give 6e.9a-difluoro-1lfi,21-,dihy,-

droxy 1,4-pregnadiene-3,20-dione 21-hemisuccinate, a crystalline solid.

Similarly, substitution of the corresponding 9mchloro or 9a-bromo startingsteroid in the above reaction of EX- ample 6B produces 6u-flL10I'O-90c-ChlOI'O-1113,21-dihydr0XY- .1,4-pregnadiene-3,20-dione 2l-hemisuccinate and its 9a- .bromo analogue, respectively.

Similarly, by .reacting 6a,9u-difluoro-11,3,2l-dihydroxy- 1,4-pregnad.iene-3,20-dione (or the corresponding 90:- chloro or 9u-bromo analogue thereof) with the appropriate hydrocarbon carboxylic acids, or the acid anhydrides and acid halides thereof, there are :produced other 17- acylates of 604,904 difluoro-1113,21-dihydroxy-1,4-pregnadiene-3',20-dione (and the corresponding 9a-chloro and 9u-bromo analogue thereof, respectively), such as 6a,9adifluoro 11,8,21 dihydroxy-1,4-pregnadiene-3,20-dione 21 formate, 6a,9a-difluoro-11,3,21-dihydroxy-L4 pregnadiene 3,20-dione 21:proprionate, 60,9oc difluoro-11 8, 21-dihydroxy-1,4-pregnadiene-3,20-dione 21-butyrate, 60:, 9a difluoro-11,8,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-va1erate, '6a',9a-difluoro-1 1 6,21-dihydroXy-1,4-pregnadiene-3,20-dione 21-hexanoate, 6u,9a-difluoro-11,B,2l-dihydroxy-l,4-pregnadiene-3,20-dione 21-laurate, 60:,9nc-ditrimethylacetate, 6a,9a difluoro-11fi,21-dihydroxy-1,4- pregnadiene-3,20-dione '21-isobutyrate, 6oc,9ozdiflu0r0-1 1 3, 21 dihydroxy-l,4-pregnadiene-3,20-dione '21-isovalerate, 600,9 difluoro 115,21-dihydroxy-1,4-pregnadiene-3,20- dione 21 tertiarybutyl-acetate, 6a,9a-difluoro-1118,21-dihydroXy-l,4-pregnadiene 3,20-dione '21-(/3-cyclopentylpropionate') 6u,9m-difluoro-1 15,21-dihydroxy-1,4pregnadiene- 3,20 .dione 21-cyclohexane carboxylate, 60,9a-difil1010- 115,21 dihydroxy-1,4-pregnadiene-3,ZO-dione 21-cyclo- 'hexylacetate, 6a,9a-difluoro-115,21-dihydroXy-1,4-pregna pregnadiene-3,20-dione 21-undecolate,'6a,9a-difiuoro-11 8,

21 dihydroxy-l,4-pregnadiene-3,20-dione ZI-cinnamate, 6a,9a difluoro l15,2l-dihydroxy-l,4-pregnadiene-3,20- dione 21-maleate, and 6a,9u-difluoro-115,21-dihydroxy- 1,4-pregnadiene-3,20-dione 21-citraconate.

If the corresponding acylating agent is solid an inert solvent such as toluene, xylene, or dioxane can be added to eflfect solution and provide a liquid esterification medium.

If'the esterifying agent is the free acid, the reaction is carried out in the presence of an esterification catalyst.

Following the esterification procedures of Examples 6A and 6B but substituting 6a,9a-difluoro-11;3,21-dihydroxy-4-pregnene-3,20-dione (and the corresponding 9achloro and 9a-bromo analogue thereof, respectively) for 6a,9u difluoro 115,2l-dihydroxy-1,4-pregnadiene-3,20- .dione is productive of the 21-acylates of 6a,9a-'Clifll101'O- 11,8,2'1 dihydroxy-4-pregnene-3,20-dione (and the corresponding9a-chloro and 9a-bromo analogue thereof, respectively) such as, for example, the 21-acetate, the 21- propionate, the 21-hemisuccinate, the 21- benzoate and the 21-(13-cyclopentylpropionate) EXAMPLE 7 difluoro 115,21 dihydroxy 1,4 pregnadiene- 3,20-dione 21 -hemisuccinate sodium salt Sodium hydroxide solution (0.1 Normal) is slowly added to a stirred solution of 100 millgrams of '6u,'9udifluoro- 1119,21 dihydroxy-l,4-pregnadiene 3,20-dione 'ZI-hernisuccinate, dissolved-in two milliliters of acetone until the'pH rises'to about 7.4. During'the addition of the sodium hydroxide solution, five milliliters of Water is also added. The solution is then concentrated at about 25 degrees centigrade under vacuum to remove the acetone. "The resultingaqueous solution of 6u,9a'-difluorol13,21-dihydroxy-1,4-pregnadiene-3,ZO-dione 21-hemisuccinatesodium salt is filtered and freeze-dried to give pure 611,90: difluoro 115,2l-dihydroxy-l,4-pregnadiene-3,20- dione 21'-hemisuccinate sodium salt.

Similarly, substitution of the corresponding 9oc-Chl01'0 or 9oc-b10Il'lO starting steroid in the above reaction of Example 7 is productive of 6a-fluoro-9a-chloro-l1,3,21-dihydroxy-l,4-pregnadiene 3,20-dione ZI-hemisuccinate sodium salt and its'9a-bromo analogue, respectively.

Substitution of the 21 hemisuccinate of Gaye-difluoro- 115,21-dihydroXy 4-pregnene-3,20-dione' (or the corresponding 9oz-chloro or 9a-bromo analogues thereof) for the ZI-hemisuccinate of 6a,9zx-difiuoro-115,21-dihydroxy- 1,4-pregnadiene-3,20-dione is productive of 6u,9a-difluoro- 1 15,21-dihydroXy-4-pregnene-3,20-dione 2 l-hemisuccinate sodium salt (and the corresponding 9a-chloro and 9abromo analogue thereof, respectively).

EXAMPLE 8 6a,9a-difluor0-2]-hydr0xy-1,4-pregnadiene- 3,11,20-tri0ne (IX) Substituting '6a,9a-difiuoro-21-hydroXy-4-pregnene-3 ,11, ZO-trione (VII) for 6a,9u-difluoro-1lfi,2l-dihydroxy-4- p're'g'nene-SJO-dione (VI) in the procedure of Example 6 is productive 'of 6a,9a-difluoro-21 hydroXy 1,4-pregnadiene-3,11,20-trione, a crystalline solid.

Likewise, the other microorganisms and enzymes listed in Example 6 canbe used to introduce a A bond into 6a,

Similarly, substitution of the corresponding 9a-chlo'r'o or 9u-br'omo starting'steroid in the above reaction pro; duces 6u-fiuoro-9a-chloro-2l-hydroxy-1,4-pregnadiene 3,

'20-dione and its 9a-bromo analogue, respectively.

EXAMPLE 8A Substituting 6a,9a-difluoro-21-hydroXy-4-pregnene-3,11, 20-trione 2l-acetate (or other 21-acylates) for 6 x,9rxdifluoro-11/3-2l-dihydroXy-4-pregnene-3,20-dione in the procedure of Example 6 is productive of 6a,9oL-difill0l'0 2l-hydroxy-1,4-pregnadiene-3,ll,20-trione (IX) which is then esterified according to procedure disclosed in EX- ample 6A to .yield 6a,9a-difluoro-21-hydroxy-1,4-pregnadiene3,20-dione ZI-acetate, a crystalline solid.

Similarly, substitution of the corresponding 9a-chloro or 9oc-bl0ll10 starting steroid produces 6a-fiuoro-9a-chloro- 21-hydroxy-l,4-pregnadiene-3,ZO-dione 2l-acetate and its 9a-bromo analogue, respectively. 1

EXAMPLE 8B 6cc,9a-difluoro-2-l-hydr0xy-1,4-pregnadiene-3,11,2O- trione 21 -hemisuccinate (IX) Substituting 6a,9a-difluoro-2l-hydroxy-1,4-pregnadiene- 3,11,20-trione (IX) for 6u,9a-difiuoro-l1,8,2l-dihydroxy- 1,4 pregnadiene-3,20-dione (VIII) in the procedure of Example 613 is productive of 6u,9a-difiuoro-2l-hydroxy- 1,4-pregnadiene- 3,11,20-trione 21-hemisuccinate, a crystalline solid.

Similarly, substitution of the corresponding 9a-chloro or 9a-bromo starting steroid in the procedure of Example 6B produces 6a-fluoro-9a-chloro-21-hydroxy-l,4-pregna- 'diene-3,11,20-trione 2l-hemisuccinate and its 9a-bromo pregnadiene-3,11,20-trione (and the corresponding 90.-

chloro and 9a-brotno analogue thereof, respectively), with the appropriate hydrocarbon carboxylic acids (in thepresence of an esterification catalyst), or the acid anhydrides and acid halides thereof, such as thosenamed above, there are produced other 17-acylates of 6a,9a-difluoro-21-hydroxy-l,4-pregnadiene-3,11,20-trione (and the corresponding 9a-chloro and 9a-b10m0 analogue thereof, respectively) such as, for example, the 21-acetate, the 21-propio- .nate, the 21-hemisuccinate, the 21-benzoate and the 21-(5- cyclopentylpropionate If the corresponding acylating agent is solid, an inert solvent such as toluene, xylene, or dioxane can be added to efiect solution and to provide a liquid esterification medium.

If the esterifying agent is the free acid, the'reaction is carried out in the presence of an esterification catalyst.

Following the esterification procedures of Examples 6A and 6B but substituting 6a,9a-difluoro-21-hydroxy-4- ,pregnene-3,1l,20-trione (and the corresponding 9u-chloro or 9a-bromo analogue thereof, respectively) for 6a.,9adifluoro-l15,21-dihydroxy-1,4-pregnadiene-3,20 dione is productive of the 21-acylates of 6a,9 x-difluoro-21-hydroxy-4-pregnene-3,11,20-trione (and the corresponding 9a-Chl0r0 or 9ct-b1'0t110 analogue thereof, respectively) such as, for example,-the -21-acetate, the 21-propionate,

the 21-hemisuccinate, the 21-benzoate and the 21-(5-cyclopcntylpropionate) EXAMPLE 9 6a.,9az-diflu0r0-21-hydr0xy-I,4-pregnadiene-3,I1,20- trione 21 -hemisuccinate sodium salt Substituting 6a,9a-difluoro-2l-hydroxy-l,4-pregnadiene- 3,11,20-trione 21-hemisuccinate (or the corresponding 9u-chloro or 9a-bromo analogues thereof) for 6a,9a-difiuoro-l15,21-dihydroxy-1,4-pregnadiene-3,20 dione 21- hemisuccinate in the procedure of Example 7 is productive of crystals of 6a,9a-difluoro-2l-hydroxy-l,4-pregnadiene- 3,11,20-trione 21he'misuccinate sodium salt (and the corresponding 9a-chloro or 9a-bromo analogue thereof, respectively).

Substitution of the 2l-hemisuccinate of 6a,9a-difiuoro- 2l-hydroxy-4-p'regnene-3,11,2 -trione 21 hemisuccinate (and the corresponding 9u-Chl010 or Qua-bromo analogue thereof, respectively) for the 2l-hemisuccinate of 60:,911- difluoro-l15,21-dihydroxy-1,4-pregnadiene-3,2O dione in the procedure of Example 7 is productive of 60,9a-difluoro-Z1-hydroxy-4-pregnene-3,20-dione 21 hemisuccinate sodium salt (and the corresponding 9a-chloro or 90:-

- bromo analogue thereof respectively).

EXAMPLE 10 6,9a-diflu0r0-2I -hydroxy-1,4-pregnadiene-3,1 1,20 trione (and the 21 -acylates thereof) (IX) from 6a,9ot-diflll0r0- 115,21-dihydr0xy-I,4-pregnadiene-3,20-dione (and the 21 -acylates thereof) (VIII) 16 EXAMPLE 11 6u,9a.-diflu0ro-I I 5,21 -dihydroxy-I ,4 pregnadiene 3,20- dione acetate (VIII) (Chemical Dehydrogenation) A mixture of 100 milligrams of 6a,9a-difiuoro-115,2ldihydroxy-4-pregnene-3,20-dione acetate dissolved in six milliliters of tertiary butyl alcohol and 0.55 milliliter of acetic acid is heated together with thirty milligrams of selenium dioxide to approximately degrees centigrade under stirring for a period of about 24 hours. Thereafter another 30-milligram portion of selenium dioxide is added and the mixture is heated to about 75 degrees Centigrade under continuous stirring for a further period of 24 hours.-

thereof) in the above reaction is productive of the Gcz,9oc- 'difluoro-115,21 dihydroxy 1,4 pregnadiene -3,20-dione (and other 21-acylates thereof).

Similarly, substitution of the corresponding 9lx-Chl01'0 or 9a-bromo starting steroids in the above reaction produces Gu-flHOIO-Qot-ChlOIO- 1 15,21-dihydroxy-1,4-pregnadiene-3,20-dione acetate (and other 21-acylates), 6a.- 'fluoro-9a-chloro-l15,21-dihydroxy 1,4-pregnadiene-3,20-

30 dione and their 9u-bromo analogues, respectively.

EXAMPLE 12 6 a,9a-diflu0r0-2I -hydroxy-I ,4-pregnadiene-3,I I ,20- trione (IX) (Chemical Dehydrogenation) Substituting 6a,9a difluoro-21 hydroxy-4 pregnene- 3,11,20 trione acetate for 611,90: difluoro-115,2l dihydroxy-4-pregnene3,20-dione acetate in the procedure of Example 11 is productive of 6a,9a-difluoro-2l-hydroxy- 1,4-pregnadiene-3,11,20-t1'ione acetate.

In like manner, substituting 6a,9a-difluoro-21-hydroxy- 4-pregnene-3,11,20-trione (and the 21-acylates thereof) in the above reaction is productive of 6a,9 x-difluoro-21- hydroxy-l,4-pregnadiene-3,11,20-trione (and the 21- acylates thereof).

Similarly, substitution of the corresponding 9a-chloro or 9a-bromo starting steroid in the procedure of Example 11 produces 6u-fluoro-9a-chloro-21-hydroxy-1,4-pregnadiene-3,11,20-trione acetate (and other 21-acylates), 6afiuoro-9u-chloro 21-hydroxy-1,4 pregnadiene 3,11,20- t'rione and their 9u-bromo analogues, respectively.

EXAMPLE 13 6a-fluor0-115,21-dihydroxy-1,4-pregnadiene-3,20-di0ne (XI) (Biological Dehydrogenation) EXAMPLE 13A 6a-fluor0-I I 5,21 dihydroxy-1 ,4-pregnadiene-3,20-dione 21 -acetate (XI) Substituting 6ocflUO1'O-1 15,21 dihydroxy 4 pregnene- 3,20-dione 21-acetate (or other 21-acylates) in the proce-, dure of Example 6 is productive of 6u-fluoro-115,21-dihy- 'droxy-1,4-pregnadiene-3,ZO-dione (XI).

Substituting 6u-fluoro 115,21 4 dihydroxy-1,4 pregnadiene-3,20-dione (XI) 7 for 6a,9a-difluor0-115,2l-dihydroxy-l,4-pregnadiene-3,20-dione (VIII) in the esterification procedure of Example 6A is productive of 6a-fluoro- 115,21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate, a crystalline solid.

EXAMPLE 13B 'da-fluoro-ll 5,21 -dihydroxy-1 ,4-preg nadiene-3,'20-dione 21 -hemisuccinate (XI) pregnadiene-3,20-dione in the procedure of'Example 6B is productive of fiwfluoro-l1,3,21-dihydroxy-1,4-pregna- 'carboxylic acids (in the presence of an esterification catalyst), or the acid anhydrides and acid halides thereof, suchas those named above, there are produced other 21'-acylates of 6a'-fluoro 1113,21 dihydroxy 1,4-pregna- 'diene-3,20-dione, such-as, for example, the -21-propionate,

the 21-(p-cyclopentylpropionate), andthe 21-benzoate.

EXAMPLE 14 6 a-fluoro-I l 5,21 -dihydmxy-I ,4-pregnadierte-3,20-dione acetate (XI) (Chemical Dehydrogenation) Substituting 6a fluoro-l118,21-dihydroxy-4-pregnene- 3,20-dione acetate for 6a,9a-difiuoro-11B,21-dihydroxy 4- pregnene-3,20-dione acetate in the procedure of Example 11 produces Gu-fluoro-lloll-dihydroxy-1,4 pregnadiene- 3,20-dione acetate, a crystalline solid.

In like manner, substituting 6a-fluor0 11,9,21-dihydroxy- 4-pregnene-3,20-dione (and the 21-acylates thereof) in the procedure of Example 11 is productive of 6a-fluoro- 1118,2l-dihydroxy-l,4-pregnadiene-3,ZO-dione (and the 21- acylates thereof).

EXAMPLE 6a-fluoro-21-hydr0xy-1 ,-'4,9 (1 1 )-pregnatriene-3,20-dione 21 -acetate (XII) Substituting 6d-.fluoro-21 hydroxy 1,4,9(11) --pregnatriene-3,20-dione 21-acetate (and other 21-acylates thereof) (XII) for 6a-,fluoro-.21-hydroxy-4,9( 1 1 -pregnadiene- 3,20-dione 21-acetate (III) in the procedure of Example 2 produces crystals of 6a-fluoro-9a-bromo-1.1,8,2l-dihydroxy-l,4-pregnadiene-3,20-dione 21-acetate (and other 2l-acy1ates thereof) (XIII).

Similarly, substitution of another N-haloamide or an N-haloimide. such as N-iodosuccinirnide or N-chlorosuccinimide for the N-bromoacetamide in the procedure of Example 2 is productive of the corresponding 9a'i0d0 or 9a-chloro product, respectively.

In like manner, substituting 6a-fluoro-21-hydroxy-1,4,- 9(11)-pregnatriene-3,20-dione in the procedure of Example 2 is productive of 6u-fiuoro-9u-bromo-l15,21-dihydroxy-l ,4-pregnadiene-3,20-dione'.

Substituting 6a-fiuoro-9a-bromo-11,9,21-dihydroxy-L4- pregnadiene-3,20-dione (and the 21-acylates thereof) (XIII) for 6a-fluoro-9a-bromo-l15,21-dihydroxy-4-pregnene-3,20-d ione (IV) in the procedure of Example3 propregnadiene-LZO-dione (and the 21-acylates thereof) (XIV)- Similarly, 6a-fluoro 9oz chloro-11/3,21-dihydroxy-1,4- preg'nadiene-3,20-dione (and the 21-acylates thereof) and the 9a-i0d0 analogue thereof can be converted to 6a.- fluoro-9;3,11B-oxido 21-hydroxy 1,4 pregnadiene 3,20- dione' (and the 21-acylates thereof).

EXAMPLE 18 Substituting 6ot-fluO1'O-9fl,11]3-0Xid0 21 hydroxy -'1,,4- pregnadiene-3,20-dione (and the 21-acylates thereof) (XIV) for 6a-fiuoro-9p,1IB-oxido-Zlrhydroxy-4-pregnene- 3,20-dione (V) intheprocedure of Example 4 produces 6a,9udiflu0r0 115,21 dihydroxy 1;4-preg'nadiene-3,20- dione (and the ZI-acylatestherof) (VIII).

Substitution of'aqueous hydrogen chloride or'hydro'gen bromide for hydrogen fluoride is productive of the'corresponding 9a-halo product.

EXAMPLE 19 The 6fl-epimers Substituting GB-fluoro 116,21- dihydroXy-4-pregn'ene- 3,20-dione 2l-acetate(and other 21-acylates) for thestarting material in Example 1 and following the procedures of Examples 1 through 18 but maintaining near'rieutral reaction conditions, there is produced respectively as the product of each example'thecorresponding Git-steroid, for example, 6,8-fluoro-2l hydroxy-4,9(11)-pregnadiene-3,20- dione 2l-acetate (and other 2l-acylates and the 2I-alcohol thereof) (Examples 1 and 1A), 6B-fiuoro-9u-bromo-l1,8,21- dihydroxy-4-pregnene-3,20 dione 21-acet'ate (a'nd other 2l-acylates and the 2l-alcohol thereof) (Example 2), 6,8- fluoro-9B,ll ,8-oxido-21-hydroxy 4 pregnene-3,20-dione (and the 21-acylates thereof) (Example 3), 6B,9m-difluoro- 1118,21-dihydroxy 4 pregnene 3,20-dione (and the 21-acylates thereof) (Example 4), 65,9a-difluor0-2l-hydroxy-4- pregnene-3,ll,20-trione -2l -acetate (and other ll-acylates and the 21-alcohol thereof) (Example 5), 6fi,9oc-difl1101'0- 11,8,2l-dihydroxy-1,4-pregnadiene-3,20-dione (Examples 6, 11, 18), 6fl,9a-difiuoro-11fi,21-dihydroXy-1,4-pregnadiene- 3,20-dione 21-acylates (Examples 6A, 6B, 11, 18), 6,9,9adifluoro-2l-hydroxy-1,4-pregnadiene-3, 1 1,20-trione (Examples 8, 10, 12), 6B,9a-difluoro-21-hydroxy-1,4-pregnadiene-3,1l,20-trione 21-acylates (Examples 8A, 8B, 10, 12), 6/3-fluoro-11,8,21-dihydroxy-4-pregnene 3,20 dione (Examples 13, 14), 6'fl-fluo'ro-l13,21'-dihydroXy-1,4-pfegnadiene-3,20-dione 21-acylates (Examples 13A, 13B, 14), 6B-fiuoro-2l-hydroxy-1,4,9(1l)-pregnatriene 3,20 dione 2l-acetate (and other 21-acylates and the 2l-alcohol thereof) (Example 15), GB-fluoro-Qa-bromo-llB,21-dihy droxy-l,4-pregnadiene-3,20-dione 21-acetate (and other ZI-acylates and the 21-alc'ohol thereof) (Example 16), 6;8-fluoro-9,B,1lp-oXido-Z1-hydroxy-1,4 pregnadiene 3,20- dione (and the 2l=acylates thereof) (Example 17).

EXAMPLE 20 Isomerizatiort of the 6;3-fluoro steroids to the corresponding 6a-flu0r0 steroids Illustratively, this reaction is carried out as follows:

A solution of one gram of 6fi,9zx-difluOrO-l 1,6,21-dihydroxy-l,4-pregnadiene-3,20-dione in milliliters of chloroform and 0.1 milliliter of alcohol is cooled to approximately minus ten degrees in an ice-salt bathand a stream of anhydrous hydrogen chloride is gently bubbled through the solution for about 2.5 hours whilst maintaining the temperature between approximately minus five and minus fifteen degrees centig'rade. The solutionis then washed with dilute sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and "evaporated to dryness under reduced pressure. Crystallization duc'es crystals of 6=fluoro-9,3,1lp-oxido-Zl-hydrdXy-IA- 5 of the residue from acetone-skellysolve' B hexanes yields 641,95 difluoro- 1 15,2l-dihydroxy-1,4-pregnadiene3,20-di- 9-bromo-115,2l-dihydroxy 1,4 pregnadiene-3,20-dione (and the 2l-acylates thereof), and 65-fiuoro-95,115-oxido- 2l-hydroxy-l,4-pregnadiene-3,20-dione (and the 21-acylates thereof) can be converted to their correspondin 60:- analogues.

This application is a continuation-in-part of application Serial No. 699,507, filed November 29, 1957.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims. 3

We claim:

1. A 6-fluoro-11-oxygenated compound of the following formula:

CHiOR wherein the 1,2-carbon atoms linkage is selected from the group consisting of single and double bond linkages, R isselected fi'om the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, X is selected from the group consisting of the carbonyl radical and the hydroxyemethylene radical, and Y is a halogen having an atomic weight of from nineteen to eighty.

2. 65,911 difluoro 115,21 dihydroxy 4 pregnene 3,20-dione.

3. 6,90; difluoro 115,21 dihydroxy 4 pregnene- 3,20-dione 2l'acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

4. 6u,9a difluoro 115,21 dihydroxy 4 pregnene- 3,20-dione 21-acetate.

5. 6a,9a difluoro 115,21 dihydroxy J 4 pregnene- 3,20-dione ZI-hemisuccinate.

, 6." 6a,9a difluoro 21 hydroxy 4 pregnene 3,11, ZO-trione.

7. 6,913 difluoro 21 hydroxy 4 pregnene 3,11, ZO-tn'one 21-acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing irom one to twelve carbon atoms, inclusive.

8. 61,95 difluoro 21 hydroxy 4 pregnene 3,11,

ZO-trione 21-acetate.

9. 602,90: difluoro 21 hydroxy 4 pregnene 3,11, ZO-trione 21-hemisuccinate.

10. 611,901. difluoro J 115,21 dihydroxy 1,4 pregnadiene-3,20-dione.

11. 6,90: difluoro 115,21 dihydroxy 1,4 pregnadiene-3,20-dione 21acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

12. 6a,9a difluoro 115,21 dihydroxy 1,4 pregnadiene-3,20-dione 21-acetate.

13. 60:,9a J difluoro 115,21 dihydroxy 1,4 pregnadiene-3,20-dione ZI-hemisuccinatc.

14. 6a,9u difluoro 21 hydroxy 1,4 pregnadiene- 3,1 1,20-trione.

15. 6,91: difluoro 21 hydroxy 1,4 pregnadiene- 3,11,20-trione 21-acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

16. 6a,9m difluoro 21 hydroxy 1,4 pregnadienc- 3,11,20-trione 21-acetate.

-17.- 65,90: J difluoro 21 hydroxy 1,4 pregnadiene- 3,11,20-trione 2l-hemisuccinate.

18. 6a tluoro 9a 'bromo .ll5,2l dihydroxy 4 pregnene-3,20-dione. I

19. 6a 4 fluoro 9a bromo 115,21 dihydroxy 4= pregnene-3,20-dione 21-acetate.

20. 6oz fluoro 9a bromo 115,21 dihydroxy 1,4- pregnadiene-3,20dione.

21. 6oz fluoro c bromo 115,21 dihydroxy 1,4- pregnadiene-3,20-dione Ill-acetate.

22. A 6 -fluoro-95,115-oxido compound of the following formula:

CH; I

wherein the 1,2-carbon atom linkage is selected from the group consisting of single and double bond linkages, and R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

23. 6e fluoro 95,115 oxido- 21 hydroxy 4- pregnene-3,20-dione.

24. 60: J fluoro 95,115 oxido 21 hydroxy 4- pregnene-3,20-dione 2l-acetate.

25. 6a fluoro 95,115 oxido 21 hydroxy 1,4- pregnadiene-3,20-dione.

26. 6:: J fluoro 95,115 oxido 21 hydroxy 1,4- pregnadiene-3,20-dione 2l-acetate.

27. A 6-fluoro-9(11)-dehydro compound of the following formula:

$HOR C=O OH? I wherein the 1,2-carbon atom linkage is selected from the p) cpg i ins o s gle an double bond linkages, and

R is selected from the group consisting of hydrogen and the 'acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

28. 60: fluoro 21 hydroxy 4,9(11) pregnadiene- 3,20-di0ne.

29. 6a fluoro 21 hydroxy 4,9(11) pregnadicne- 3,20-dione ZI-acetate.

30. 6a 4 fluoro 21 hydroxy 1,4,9(11) pregnatriene- 3-20-dione.

31. 60c fiuoro 21 hydroxy 1,4,9(11) pregnatriene- 3,20-dione 21-acetate.

No references cited. 

1. A 6-FLUORO-11-OXYGENATED COMPOUND OF THE FOLLOWING FORMULA:
 22. A 6 FLUORO-9B, 11B-OXIDO OF THE FOLLOWING FORMULA: 